Published online: 13.12.

2019

High-Risk Pregnancies and Their Impact on

Neonatal Primary Hemostasis
Marianna Politou, MD, PhD1,
Vasiliki Mougiou, MD, PhD(c)2,
Maria Kollia, MD, PhD(c)2
Rozeta Sokou, MD, PhD2 Georgios Kafalidis, MD, PhD2 Zoi Iliodromiti, MD, PhD2
Serena Valsami, MD, PhD1 Theodora Boutsikou, MD, PhD2 Nicoletta Iacovidou, MD, PhD2

1 Hematology Laboratory-Blood Bank, Aretaieio Hospital, National Address for correspondence Nicoletta Iacovidou, MD, PhD, Medical
and Kapodistrian University of Athens, Athens, Greece School, Aretaieio Hospital, National and Kapodistrian University of
2 Neonatal Department, Aretaieio Hospital, Medical School, Athens, 76, Vasilissis Avenue, Athens 11528, Greece
National and Kapodistrian University of Athens, Athens, Greece (e-mail: niciac58@gmail.com).

Semin Thromb Hemost

Abstract Primary hemostasis, similar to other systems in the adjusting and transitioning
neonate, undergoes developmental adaptations in the first days of life. Although

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Keywords
► platelets
► platelet function
► neonates
► primary hemostasis
► high-risk pregnancies
► neonatal hemostasis
platelets of neonates do not differ quantitatively compared with those of adults, they
functionally present with major differences, thus supporting the theory of a “hypofunc-
tional” phenotype that is counterbalanced by high hematocrit and more potent von
Willebrand factor multimers. No clinical effect of bleeding tendency has hence been
established so far for healthy term neonates. However, discrepancies in functionality
have been noted, associated with gestational age, with more pronounced platelet
hyporesponsiveness in preterm neonates. Multiple methods of in vitro platelet function
evaluation such as PFA-100/200, platelet aggregometry, flow cytometry, and cone and
platelet analyzer have been used for assessment of neonatal primary hemostasis.
Several pregnancies are characterized as “high-risk” when risk factors preexist in
maternal history or evolve during pregnancy. These pregnancies require specialized
observation as they may have unpredictable outcome. High-risk pregnancies include
clinical entities such as preeclampsia, pregnancy-induced smoking during pregnancy,
gestational diabetes mellitus (GDM), autoimmune diseases, and other maternal
hematological conditions. In some cases, like systemic lupus erythematosus, anti-
phospholipid antibody syndrome, and maternal immunologically based thrombocyto-
penia, neonatal thrombocytopenia is regarded as a prominent hemostasis defect, while
in others, like pregnancy-induced hypertension and preeclampsia, both quantitative
and qualitative disorders of neonatal platelets have been reported. In other patholo-
gies, like GDM, neonatal primary hemostasis remains vastly unexplored, which raises
the need for further investigation. The extent to which primary hemostasis is affected
in neonates of high-risk pregnancies is the main objective of this narrative review.

Neonatal hemostasis has been a field of great interest over
the past few decades as recognition has grown of the many
dynamic changes that occur during the transitional stage


Politou and Mougiou shared first authorship.
from fetal to neonatal life. Although the coagulation system
has been thoroughly studied in the neonatal population,
there are still several issues that have yet to be elucidated,
particularly regarding primary hemostasis in this age group.
Platelets play a key role in human hemostasis, as they adhere

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High-Risk Pregnancies and Their Impact on Neonatal Primary Hemostasis Politou et al.

to the vascular endothelium at sites of injury, and thereafter
become activated and secrete a variety of prohemostatic
agonists, a process that leads to their aggregation and
formation of a primary hemostatic plug. With a lifespan of
5 to 7 days, platelets originating from the bone marrow-
derived megakaryocytes (MKs) circulate in blood vessels
until active recruitment, via interaction of their membrane
glycoprotein (GP) Ib/IX/V complex and plasma von Wille-
brand factor (VWF), together with subendothelial matrix
components. This initial interaction slows the flow of plate-
lets and allows other platelet receptors (GPVI and integrin
α2β1) to bind to collagen.1–4 Secondary to adhesion, a change
of platelet shape leads to platelet aggregation via platelet-to-
platelet interactions (the GPIIb/IIIa receptor [also termed
integrin αIIbβ3] binding fibrinogen), while transduction
of secondary signals leads to degranulation and release of
mediators from the platelet granules that act as platelet
agonists, including thromboxane A2 (TXA2), adenosine
diphosphate (ADP), and thrombin.5,6 These agonists elicit
Several methodologies (see ►Table 1) have been used for
assessing neonatal primary hemostasis, but reference
ranges, especially age-specific, have not yet been officially
established. The aim of the present narrative review is to
summarize current knowledge on primary hemostasis
(platelet quantitative and qualitative characteristics) in
normal neonates as well as in neonates from high-risk
pregnancies. High-risk pregnancies represent cases of high
interest as they require special management and close
observation (see ►Table 2). Almost 15% of all pregnancies
could be characterized as “high-risk” due to potentially life-
threatening complications. The most frequently encountered
are pregnancies complicated with high blood pressure,
diabetes mellitus, preeclampsia, and infections. Preexisting
maternal medical conditions or factors such as obesity and
age may define a pregnancy as potentially of high risk. Risk
factors appearing during any stage of pregnancy may have an
impact on the hemostatic system and compromise both
maternal and neonatal well-being. We review the literature

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further activation of platelets by expression of adhesion
molecules like P-selectin, leading to platelet–platelet inter-
actions and inducing inflammatory reaction with recruit-
ment of leukocytes via cytokine and chemokine secretion.
Platelet aggregates, also known as white thrombi, form the
primary clot.7,8
In neonates, it has been found that platelet counts present
no difference in absolute number compared with adults, but
studies support a major discrepancy in their functionality,
toward a more hyporesponsive phenotype compared with
adult platelets.9,10
for the impact of these aforementioned conditions (chosen
because of their frequency and clinical significance) on
neonatal primary hemostasis and the implicated mecha-
nisms are discussed.11,12
Primary Hemostasis in Neonates
Platelet production begins as early as 5 weeks postconcep-
tion, when MK progenitors are found in the liver and platelets
in the fetal circulation.13 The four steps in platelet production
as described by Martha Sola-Visner include: production of

Table 1 Methods for assessing platelet function

Method Principle Tests reported in neonates

Bleeding time (BT) In vivo screening test for the interaction between platelets and Gerrard et al, 1989133
the blood vessel measuring the time needed to form a Del Vecchio and Sola, 200047
hemostatically effective platelet clot (Andrew et al 1989132) Sola et al, 200148
Del Vecchio, 200245
Del Vecchio et al, 200846
Sheffield et al, 2011134
Platelet Agonist-specific platelet aggregation measured by changes in Gader et al, 198850
aggregometry light transmission50 Uçar et al, 200538
Bonduel et al, 2007135
Tanous et al, 2017136
Flow cytometry Monoclonal Rajasekhar et al, 1994, 199735,138
antibodies that bind platelet activation markers and other Pietrucha et al, 2001139
surface glycoproteins via flow cytometry137 Saving et al, 2002140
Hézard et al, 2003141
Sitaru et al, 2005150
Wasiluk et al, 2008142
Baker-Groberg et al, 2016143
Cone and platelet In vitro whole blood assessment of platelet adhesion and Shenkman et al, 1999144
analyzer (CPA) aggregation under high shear conditions by measuring platelet Linder et al, 2002145
surface coverage (SC) on the viscometer53 Levy-Shraga et al, 200654
Strauss et al, 2010 70
Platelet function In vitro whole blood assessment of platelet activation and Carcao et al, 1998146
analyzer aggregation under high shear conditions and exposure to Israels et al, 2001147
(PFA-100/200) different agonists by measuring closure time (CT) required to Roschitz et al, 200156
occlude an aperture55 Boudewijns et al, 200340
Saxonhouse et al, 201058

Seminars in Thrombosis & Hemostasis

 High-Risk Pregnancies and Their Impact on Neonatal Primary Hemostasis Politou et al.

Table 2 High-risk pregnancies affecting primary hemostasis

Pregnancy-induced Pregnancy-induced hypertension (PIH) is persistent de novo hypertension that develops at or

hypertension (PIH) after 20 weeks’ gestation in the absence of features of preeclampsia148
Preeclampsia Preeclampsia is gestational hypertension accompanied by at least one of the following
new-onset conditions at or after 20 weeks’ gestation:
Proteinuria
Other maternal organ dysfunction (acute kidney injury, liver involvement, neurological
complications, hematological complications)
Uteroplacental dysfunction148
HELLP syndrome Acronym for hemolysis (H), elevated liver enzymes (EL), and low platelet count (LP)148
Smoking during pregnancy
Systemic lupus Transplacental passage of maternal immunoglobulin G (IgG) autoantibodies against Sjögren’s
erythematosus (SLE) / syndrome autoantigens (SSA (Ro) and SSB (La)) results in neonatal lupus erythematosus
Neonatal lupus syndrome (NLES)99
syndrome (NLS)
Antiphospholipid antibody Acquired autoimmune disorder that clinically manifests with recurrent venous or arterial
syndrome (APS) thrombosis and/or fetal loss106
Gestational diabetes State of glucose intolerance of variable severity, that is only detected during pregnancy.
mellitus (GDM) GDM is diabetes that is first diagnosed in the second or third trimester of pregnancy that is

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Maternal-fetal quantitative
platelet defects
(thrombocytopenia)
not clearly either preexisting type 1 or type 2 diabetes149
Gestational thrombocytopenia (80%)
Preeclampsia and HELLP syndrome
Thrombotic thrombocytopenic purpura (TTP)
Hemolytic uremic syndrome (HUS)
Disseminated intravascular coagulation (DIC)
Immune thrombocytopenic purpura (ITP)
Alloimmune fetal-neonatal alloimmune thrombocytopenia (FNAIT)

thombopoietic factors, such as thrombopoietin (TPO), the
most important catalyst in platelet homeostasis, prolifera-
tion of MK progenitors, maturation of MKs, and production
and release of platelets into the circulation.14,15
Developmental differences between neonatal and adult
platelets have been described by several workers. Neonatal
MK progenitors exhibit higher and more rapid proliferative
capacity than adult platelets, as a result of which progenitor
MK cells generate 10-fold more MKs per cell than adults.16,17
Neonatal MKs are smaller in size and lower in ploidy than adult
MKs. Although they achieve full cytoplasmic maturation with
lower levels of ploidy, they produce lower number of platelets
per MK.18 Neonatal MKs cannot expand sufficiently in size
when demand increases in case of existing thrombocytopenia,
and they only increase in number demonstrating a reduced
mean platelet volume (MPV) and a lower platelet reactivity
compared with adult MKs that increase first by size and then
by number.19,20 Other characteristics of neonatal thrombopoi-
esis are higher TPO concentrations and greater sensitivity to
TPO than adults.21
Human platelet lifespan is estimated to be around 10 days.
Data from mice models support prolongation of neonatal
platelet survival, compared with adults, in line with
data from human in vitro analyses as well.22,23 Immature
reticulated platelets are the newest ones to be released from
the bone marrow, with high ribonucleic acid content contrary
to mature platelets. Their absolute number reflects the extent
of thrombopoiesis and is expressed as the immature platelet
fraction (IPF), which serves as an emerging biomarker for
monitoring of neonatal thrombocytopenia.24 IPF allows the
distinction between consumptive and hypoproliferative etiol-
ogies of thrombocytopenia as it is expected to be lower in the
latter where megakaryopoiesis is impeded.25 IPF may also
have predictive value regarding the management of neonatal
thrombocytopenia, since elevation of IPF indicates higher
production of young platelets and therefore it may prevent
an unnecessary transfusion.26
Platelet numbers reach normal adult hemostatic values by
the 22nd week of gestation. Hence, it has been generally
presumed that platelets do not differ significantly in number
or volume in neonates compared with adults, with values
ranging between 150 and 400  109/L and 7 and 9 fL,
respectively.27 However, Wiedmeier et al in 200928 studied
47,000 neonates with gestational age between 22 and
42 weeks and demonstrated that platelet counts increase
as gestational age advances, with the lower limits of platelet
values being lower than those of adults, especially for
premature infants. Platelet counts of term infants increase
over the first 7 to 14 days of life and remain steady for the
next 2 weeks following the pattern of plasma TPO concen-
tration, since TPO peaks on the second day of life and remains
higher than that of healthy adults during the first 2 to 3 weeks
of life.28 The overall prevalence of neonatal thrombocytope-
nia is 1 to 5%, mostly affecting preterm-neonatal intensive
care unit admitted infants, with a rate there of 22 to 35%.
More precisely, approximately 70% of all neonates born with
a body weight of < 1 kg present with thrombocytopenia,
thus increasing their risk of intraventricular hemorrhage
(IVH).29,30 However, thresholds that define thrombocytope-
nia are age-dependent.

Seminars in Thrombosis & Hemostasis

High-Risk Pregnancies and Their Impact on Neonatal Primary Hemostasis
Regarding platelet functionality, ultrastructural observa-
tions demonstrate a relative hyporesponsive pattern of
neonatal platelets, as they exhibit less microtubular struc-
tures, fewer pseudopodia, and fewer granules than adult
platelets.31 Furthermore, neonatal platelets have decreased
α and dense granule secretion, reduced expression of surface
activation markers, deficiency in phospholipid metabolism,
and reduced calcium mobilization compared with those of
adults.32,33 Receptors that bind activating platelet factors are
also fewer and this causes a limited responsiveness to
agonists like ADP, thrombin, epinephrine, collagen, and
TXA2 analogues.34 Receptor-mediated intracellular signaling
pathways also show reduced responses compared with
adults as an expression of the platelets’ immaturity that
evolves in an age-dependent manner. GPIIb/IIIa receptors are
not sufficiently expressed on the surface of neonatal platelets
and their binding is not as efficient in the activated form of
neonatal platelets as in adult platelets.35 The composition in
phospholipids of neonatal platelet membranes does not
differ from adults, thus leading to adequate production of
thrombin. Even in thrombocytopenia, endogenous thrombin
potential remains stable due to lower tissue factor pathway
inhibitor and antithrombin levels that diminish the amount
of phospholipids needed to generate thrombin.36
After the first days of life, this transient comparative hypo-
responsiveness, as directly linked to gestational age, gradually
subsides and developmental processes generate functionally
mature platelets (process of developmental hemostasis).37 The
time of complete normalization of neonatal platelet reactivity
according to most studies occurs between the 10th and 14th
day of life.37,38
Despite their hypofunctional platelets, term neonates
exhibit no clinical bleeding tendencies. Contrasting this
lowered responsiveness, neonates seem to have an overall
enhanced primary hemostasis, a finding reflected by in vitro
functional tests. This amplified hemostasis has generally been
attributed to higher hematocrit of neonates, greater mean
corpuscular volume, higher VWF levels in comparison to
adults, as well as the presence of ultralarge VWF multimers.
These factors enhance cellular interaction and adhesion of
platelets to subendothelium and altogether counterbalance
the intrinsic hypofunctionality of neonatal platelets.39–41
Platelets from premature neonates exhibit decreased plate-
let adhesion capacity and lower MPVs than term neonates,
which reflects their lower ability to produce younger reticulated
platelets.42,43 The hyporeactivity of platelets in premature neo-
nates contributes to higher risk for hemorrhagic episodes
including intracranial hemorrhage (ICH).43
Methods of Primary Hemostasis
Investigation in Neonates (see ►Table 1)
Several methods have been used in the evaluation of platelet
function, apart from the classical bleeding time (BT), and
including platelet aggregometry, platelet function analyzer
(PFA)-100/200, and the cone and platelet analyzer (CPA).
Notable challenges exist with most methodologies and the
interpretation of their results, as they evaluate predominantly
Seminars in Thrombosis & Hemostasis
Politou et al.
the ex vivo response of neonatal platelets and method stan-
dardization and age-specific reference ranges are lacking.44
Bleeding Time
Bleeding time, measuring the time required for platelets to
form a clot in a physical skin wound, has been previously
established as an efficient method to evaluate in vivo prima-
ry hemostasis.45 The BT seems to be proportionally related to
the severity of thrombocytopenia for platelet counts below
100  109/L and also appears to be more prolonged at
smaller gestational ages.46,47
Bleeding time in preterm neonates may be up to two times
as long as that of full-term neonates at the time of birth,
while at around the 10th day of life any association between
gestational age and BT ceases to exist. This solidifies the
theory that platelet functionality is inversely correlated with
gestational age and that normalization of human primary
hemostasis is a developmental process.46 However, this
method is highly invasive and has limited reproducibility,
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thus its use remains controversial due to operational vari-
ability, and it is no longer applied in most facilities.48,49
Platelet Aggregometry/Flow Cytometry
Platelet aggregometry represents a technique based on
changes that occur in optical density of platelet-rich plasma
upon agonist-induced platelet aggregation. It is not greatly
applied in neonates because of the high volume of blood that
needs to be collected.38,50
Flow cytometry uses monoclonal antibodies to detect
platelet surface GPs that serve as platelet activation markers,
such as P-selectin and the fibrinogen binding site on GPIIb/IIIa.
The methods require minimal blood volumes (5–100 μL) and
can also be used on thrombocytopenic patients; however, they
remain highly specialized and expensive.51 It has been dem-
onstrated that preterm and extremely low birth weight infants
present with reduced platelet adhesion and aggregation and
lower reactivity levels than adult platelets.43 Furthermore, the
reduced expression of surface activation markers in term
neonates compared with adults seems to persist until the
10th day of life, when neonatal platelet reactivity approaches
adult levels.52
Cone and Platelet Analyzer
The CPA induces and quantifies platelet adhesion and aggre-
gation under shear stress conditions by measuring the area
of the cone-and-plate viscometer that is covered by platelet
clots.53 The method requires a small amount of blood (200 μL
of whole citrated blood) and has corroborated the results of
other studies, concluding that faster adhesion and aggrega-
tion occurs in neonates in comparison to adults, and also
confirms an age-dependent platelet functionality.54 This
methodology, however, still remains far from being a useful
tool for clinical utility, due to its limited availability and
experience, and is thus mainly used for research.
Platelet Function Analyzer-100/200
PFA-100/200 is an in vitro, reproducible system that utilizes
small volumes of citrated whole blood, tested by using two
 High-Risk Pregnancies and Their Impact on Neonatal Primary Hemostasis
different agonist systems, epinephrine, and ADP, each com-
bined with collagen, thus leading to platelet activation and
adhesion/aggregation under shear stress conditions. The
time required for primary clot formation is referred to as
closure time (CT) for either cartridge (COL/EPI or COL/ADP)
and depicts the global platelet–VWF-related hemostasis.55
Few existing studies have compared adults and healthy term
neonates, with these demonstrating lower CTs in neonates. This
has been attributed to the presence of ultralarge VWF multi-
mers rather than to differences in cellular blood constituents,
such as higher hematocrit or more elevated white blood cell
values that prevail in neonatal populations.40,56 PFA-100/200
CTs can be influenced by factors like therapeutic hypothermia,
several medications including nonsteroidal anti-inflammatory
drugs, and postconceptional age.32,57
As far as prematurity is concerned, CTs using COL/ADP
were found to be inversely correlated with gestational age,
but no correlation was found in terms of COL/EPI CTs, thus
implying that certain (rather than all) signaling pathways
may be affected in neonatal platelet activation cascade.57
PFA-100/200 remains at present one of the most widely
used methodologies for comprehension and evaluation of
neonatal hemostasis. Limitations exist, however, such as dem-
onstration of a significantly important difference between CTs
in cord blood samples and in neonatal peripheral blood.58
High-Risk Pregnancies and Impact on the
Neonate (see ►Table 2)
Hypertensive Disorders of Pregnancy
Hypertensive disorders of pregnancy affect platelet number
and function in maternal and fetal/neonatal circulation. Plate-
lets play an important role in the maintenance of the patho-
physiology of pregnancy-induced hypertension (PIH) and
preeclampsia. The abnormal placentation causes endothelial
dysfunction through vasoactive agents released in maternal
circulation. Different pathways (e.g., decreased nitric oxide and
prostacyclin, elevated TXA2, angiotensin II, and cytokines)
promote platelet activation. The effectiveness of use of anti-
platelet agents for preventing preeclampsia in high-risk preg-
nancies provides proof for involvement of platelets in the
pathogenesis of hypertensive disorders of pregnancy.59 As far
as maternal circulation and primary hemostasis is concerned,
the total number of platelets has been found decreased in
several studies,59–63 whereas the MPV is frequently increased
in pregnancies complicated with PIH.59,63
Many studies on platelet function in pregnant women with
preeclampsia have been conducted to date. Platelet aggregation
studies demonstrated in vitro reduced platelet aggregation
in preeclamptic women, as a result of excessive in vivo activa-
tion and platelet exhaustion.63,64 The presumptive adaptation
of platelets to a previous stage of responsiveness as an attempt
to improve the uteroplacental perfusion in intrauterine growth
restricted (IUGR) pregnancies supports the theory of platelet
exhaustion and subsequent hyporesponsiveness.65 This theory
is strengthened by significantly higher expression of CD63 on
platelets’ surface of preeclamptic women during early stage
pregnancy, and implementation of this finding as a risk factor
Politou et al.
of developing preeclampsia.61,66 These findings were further
confirmed via PFA-100/200.62,67,68 However, there are studies
that failed to support a significant difference of platelet
function between normal pregnancies and pregnancies com-
plicated with PIH or preeclampsia using aggregometry68,69 or
flow cytometry.63
Few studies have been conducted on platelet function of
neonates born to mothers with preeclampsia and their
results are inconclusive. Hyporesponsiveness of platelets in
offspring of preeclamptic mothers was supported by lower
expression of GPs on platelet surfaces13 and lower platelet
adhesion using CPA.70 However, other studies using flow
cytometry exhibited higher in vitro responsiveness of plate-
lets to various agonists among this subgroup of neonates.63
Offspring of pregnancies with hypertensive disorders form a
high-risk group of neonates. The thrombocytopenia of neonates
born to mothers with PIH or preeclampsia has been well
documented since late 1970s.60,71–77 The frequency of throm-
bocytopenia in these neonates ranges from 26 to 47%, and is
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observed at birth until the 3rd day of life, and resolves at day
10.74,76 The pathophysiology of this thrombocytopenia
remains debated.78 Fetal hypoxia due to placental hypoperfu-
sion may suppress the proliferation of MKs, thus resulting in
reduction of platelet production in favor of erythropoiesis,73,76
while the consumption of platelets on a thrombotic bed of
placenta could provide another explanation.73,79 On the other
hand, Zook et al failed to connect neonatal thrombocytopenia to
placental histopathology.80 Higher incidences of thrombocyto-
penia among these infants could also be attributed either to the
higher frequency of prematurity at this subgroup of neo-
nates70,75 or only to the risk of developing small for gestational
age neonates.81 IVH is more common among infants
whose mothers were diagnosed with HELLP syndrome and a
possible defect on platelet function may contribute to this risk
above the observed thrombocytopenia.82
The American College of Obstetricians and Gynecologists
and the Society for Maternal-Fetal Medicine recommend
low-dose aspirin (81 mg/day) prophylaxis in women at
high risk of preeclampsia, initiated between 12 and 28 weeks
of gestation (optimally before 16 weeks), and continued daily
until delivery.83 Aspirin in low doses selectively suppresses
TXA2 synthesis without reducing the production of prosta-
cyclin.84 A small amount of acetylsalicylic acid reaches fetal
circulation.85 Although a reduction of TXB2 levels in umbili-
cal cord blood was documented,84–87 platelet aggregation
studies failed to demonstrate differences between the two
groups of neonates (neonates whose mothers had received
aspirin vs. neonates whose mothers had not received aspi-
rin).88,89 None of the studies reported bleeding tendency in
neonates whose mothers received daily low-dose aspirin
during pregnancy.
Smoking during Pregnancy
In utero tobacco exposure has been linked to IUGR, preterm
birth, and low birth weight infants, and is associated with an
increased risk of congenital heart disease, orofacial clefts,
respiratory infections, poorer cardiovascular and respiratory
function, increased rates of sudden unexpected infant death,
Seminars in Thrombosis & Hemostasis
High-Risk Pregnancies and Their Impact on Neonatal Primary Hemostasis
metabolic syndrome later in life, and poor neurodevelop-
mental outcome.90–92 Among adults, smokers tend to exhibit
higher platelet aggregability compared with non-
smokers93,94 but no difference of total platelet count, platelet
distribution width, MPV, or platelet large cell ratio was
confirmed between neonates of smoking and nonsmoking
mothers.95 This finding was further supported in animal
models (rats).96 However, a recent study identified shorter
CTs in neonates of smoking mothers compared with those of
nonsmoking controls.97 Moreover, although Ahlsten et al
found that platelet count was slightly lower in infants of
smoking mothers than in control infants, they failed to
document differences between the two groups, either in
the qualitative or quantitative aggregation responses, or in
TXB2 synthesis.98
Systematic Lupus Erythematosus/Neonatal Lupus
Syndrome
The transplacental passage of maternal immunoglobulin G
(IgG) autoantibodies against Sjögren’s syndrome autoantigens
(SSA (Ro) and SSB (La)) results in neonatal lupus erythemato-
sus syndrome (NLES).99 The incidence of NLES is estimated at
approximately 2% and increases in subsequent pregnancies.100
Pregnant women with systemic lupus erythematosus (SLE)
tend to have higher rates of stillbirths, gestational diabetes,
preterm pregnancies, and IUGR.99 NLES may present with
cutaneous lesions, cytopenias, and hepatic dysfunction (in
decreasing frequency), which are reversible, and with cardiac
arrhythmias and atrioventricular block, which are irrevers-
ible.100 The most frequent finding regarding neonatal platelets
is transient thrombocytopenia. The incidence varies between
4 and 30% in different studies.101,102 Although cytopenias in
NLES persist until 3 to 6 months of age, thrombocytopenia
tends to be the least frequent compared with neutropenia and
anemia.103 In the literature, there are only case reports with
thrombocytopenia as the only and main presenting symptom
of NLES.104,105
Antiphospholipid Antibody Syndrome
Antiphospholipid antibody syndrome is an acquired autoim-
mune disorder that clinically manifests with recurrent venous
or arterial thrombosis and/or fetal loss.106 Pregnant women
may experience recurrent early miscarriage, late fetal loss,
premature birth, hypertensive disorders, of pregnancy includ-
ing preeclampsia and HELLP. Defects on neonatal platelets,
mainly thrombocytopenia, are due to these clinical manifes-
tations of pregnancies.107
Gestational Diabetes Mellitus
The incidence of gestational diabetes mellitus (GDM) varies
between 9 and 26% according to the HAPO study (Hyperglyce-
mia and Adverse Pregnancy Outcomes).108 Fasting plasma
glucose, hemoglobin A1c (HbA1c), and oral glucose tolerance
test, are some of the screening strategies used to detect
GDM.109 Normal metabolic adaptations occurring during
pregnancy are exaggerated in GDM and cause resistance to
insulin and maternal hyperglycemia.110 As a consequence of
maternal hyperglycemia, fetal pancreatic tissue hypertrophy
Seminars in Thrombosis & Hemostasis
Politou et al.
and hyperinsulinism occur, which upon abrupt elimination of
maternal glucose supply after birth result in neonatal
hypoglycemia.111
Impaired fasting glucose both as a prediabetic stage and in
terms of diabetes is characterized by increased MPVs, which in
turn demonstrate a higher activation level of platelets in these
patients. MPVgenerally indicates the average size and reactivity
of platelets, with younger and more active platelets being larger
in volume. Thus, higher MPVs suggest higher prothrombotic
states and predict cardiovascular complications.112,113 Studies
in GDM have shown a positive correlation between MPV and
glucose levels, thus linking higher MPVs with poorer glycemic
control and making MPV a useful predictive marker of the
gluco-metabolic state in pregnancies.114 Increased platelet
activity as demonstrated by high MPVs is linked to persistent
hyperglycemia and insulin resistance of GDM. The mechanisms
underlying this hyperactivity are proposed to be the following:
Hyperglycemia both in GDM and in type 1 diabetes
induces aldose reductase activity, and thus activates the
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cellular polyol pathway that accumulates osmotically
active substances like sorbitol, resulting in platelet swell-
ing. This marked increase in volume leads to platelet
activation via microtubule polymerization, degranula-
tion, and enhanced thrombin formation in a collagen
milieu.115 The degree of persistent chronic hyperglycemia
is depicted by HbA1c, which serves mostly as a marker of
glycemic control and is correlated with enhanced platelet
aggregation and activation.116
The expression of GPVI collagen receptor is higher in
platelets of diabetic individuals, which makes them
hyperreactive and leads to an increased rate of cardiovas-
cular events. Reactive oxygen species production caused
by downstream of GPVI signaling is proportionally exag-
gerated in elevated glucose levels.117
Chronic hyperglycemia affects calcium homeostasis by
enhancing the calcium influx as a response to collagen
and thrombin, thus fostering platelet adhesion.118
Insulin normally exerts an antiaggregating effect on pla-
telets, by means of inhibiting calcium mobilization. In
diabetes mellitus, platelets have been reported to exhibit
insulin resistance which impairs their normal response to
the hormone and leads to platelet hyperreactivity.119,120
Regarding insulin resistance, a significant effect is exerted
on platelets, as has been demonstrated by the positive
correlation between MPV and the levels of insulin and
Homeostatic Model Assessment for Insulin Resistance in
pregnancies with GDM.121
The aforementioned studies have been conducted in
platelets from healthy adults, thus no data are available so
far on the effect of insulin and hyperglycemia in platelets
from infants or neonates. In only one study of a mixed
population of pregnancies with risk factors, was impaired
platelet adhesion detected in infants born to mothers with
GDM compared with infants born to healthy mothers.70
In terms of platelet number, platelets of infants born to
diabetic mothers have been found to be decreased compared
with control uncomplicated pregnancies during the first day
 High-Risk Pregnancies and Their Impact on Neonatal Primary Hemostasis
of life, which could be explained through a model of chronic
hypoxia induced by diabetes.122 Another possible mecha-
nism for thrombocytopenia could be high levels of leptin
found in mothers with type 1 diabetes, which may lead to
platelet consumption due to proaggregatory properties of
leptin.123
Thrombocytopenia, however, seems to be a much less
frequent complication of GDM.124
Maternal-Fetal Quantitative Platelet Defects
The incidence of thrombocytopenia in pregnancy is around 4 to
12% in all pregnancies, with values below 100  109/L found
only in 1 to 5% of all women. Thrombocytopenia in pregnancy
includes several entities, with gestational thrombocytopenia
accounting for 80% of all cases, followed by preeclampsia and
HELLP syndrome, thrombotic thrombocytopenic purpura/he-
molytic uremic syndrome, disseminated intravascular coagula-
tion, and immune thrombocytopenias. Most pathologies have a
very minimal impact on the offspring, causing neonatal throm-
bocytopenia in < 2% of all cases.125,126
Immunologically based thrombocytopenia may present as
primary immune thrombocytopenic purpura (ITP) or as
alloimmune fetal-neonatal alloimmune thrombocytopenia
(FNAIT). ITP with a pregestational history of maternal throm-
bocytopenia, accounts for only 3% of all thrombocytopenias of
pregnancy, with maternal platelet counts being < 50  109/L
during the first and second trimester in the majority of the
cases. Neonatal thrombocytopenia occurs at a rate of 10 to 15%,
with platelet counts as low as 20  109/L in 5% of these high-
risk infants, regardless of the severity of maternal thrombocy-
topenia.127 It has generally been ascertained that neonatal
outcomes are independent of maternal thrombocytopenia in
ITP, and that the presence of neonatal thrombocytopenia is
more common when prematurity is implicated.125 The onset
of thrombocytopenia due to maternal antiplatelet IgG may be
delayed up to the first week postpartum.
Immune neonatal thrombocytopenia can be also encoun-
tered in FNAIT. Platelet membrane GPs (integrins GPIbα,
GPIIb/IIIα) identified as human platelet antigens (HPAs) are
responsible for sensitization of the maternal immune system
when these specific antigens are absent from maternal plate-
lets, but present on fetal platelets through paternal inheri-
tance.128 As a result, during episodes of feto-maternal
hemorrhage or even through interaction of maternal blood
cells with antigen-positive trophoblasts, fetal HPAs act as
epitopes that trigger production of maternal antibodies, which
cross the placenta and promote fetal platelet destruction.
Leading causes are HPA-1a and 5b, while the presence of
HLA DRB3
01:01 allele increases the risk of alloantibody
formation. Unlike in ITP, FNAIT neonates present with early
thrombocytopenia (often platelets are < 50  109/L) and
bleeding symptoms, with their mothers having normal plate-
let counts.129 FNAIT is hence regarded as the platelet equiva-
lent of hemolytic disease of the fetus/newborn, although it
may also affect the first pregnancy. The incidence of this
condition is 1:1,000 to 3,000 live births, 10% of which are
complicated by severe complications like ICH.126 In case of
Politou et al.
confirmation, fetal ultrasound brain monitoring and fetal
blood sampling for platelet count are needed, followed by
platelet transfusion and intravenous Ig in the neonate if
necessary. HPA typing of both parents and neonate in conjunc-
tion with maternal alloantibody screening should be per-
formed for a prompt diagnosis of FNAIT.130,131
Conclusion
Neonatal platelet function, although marked as a develop-
mental process, represents a fully developed and effective
system of primary hemostasis that aids the neonate to cope
with the high in vivo demands of transition to the extrauter-
ine life.
High-risk pregnancies, through different and complex
pathophysiologic pathways, result in adverse events on
both mothers and their neonates and their complications
may include abnormalities in primary hemostasis.
However, the extent to which platelets of different neonatal
Downloaded by: Imperial College London. Copyrighted material.
subpopulations, such as neonates from pregnancies compli-
cated with preeclampsia, IUGR, GDM, smoking, SLE, and other
quantitative platelet defects are phenotypically functional
remains a conundrum. Several laboratory tests have been
used to characterize in detail the steps of neonatal primary
hemostasis, encompassing platelet activation, adhesion, and
aggregation, with respect to their unique features both age-
wise and according to various risk factors present during the
pregnancy. Global assessment of coagulation using a variety of
laboratory tests can promote understanding of the pathophys-
iologic mechanisms and provide the possibility for new
screening and assessment methods for high-risk mothers
and neonates. Although defects in primary hemostasis have
been evaluated in mothers, little has been achieved in the
elucidation of alterations in primary hemostasis in the off-
spring of high-risk pregnancies. Further studies are therefore
needed to clarify and characterize the neonatal platelet and
their functionality when risk factors are present.
Conflict of Interest
None declared.
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